Heterocyclic compounds and their uses

ABSTRACT

Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. application Ser. No.16/579,360, filed Sep. 23, 2019, which is a continuation of U.S.application Ser. No. 15/926,411, filed Mar. 20, 2018, now U.S. Pat. No.10,421,726, which is a divisional of U.S. application Ser. No.14/210,713, filed Mar. 14, 2014, now U.S. Pat. No. 9,951,015, whichclaims priority benefit of U.S. Provisional Application No. 61/785,763,filed Mar. 14, 2013, the disclosures of which are incorporated byreference in their entireties for all purposes.

FIELD

Provided is a pharmaceutical formulation comprising omecamtiv mecarbil,or a pharmaceutically acceptable salt, a pharmaceutically acceptablehydrate, or a pharmaceutically acceptable hydrate of a pharmaceuticallyacceptable salt thereof, such as omecamtiv mecarbil dihydochloridehydrate.

BACKGROUND

The cardiac sarcomere is the basic unit of muscle contraction in theheart. The cardiac sarcomere is a highly ordered cytoskeletal structurecomposed of cardiac muscle myosin, actin and a set of regulatoryproteins. The discovery and development of small molecule cardiac musclemyosin activators would lead to promising treatments for acute andchronic heart failure. Cardiac muscle myosin is the cytoskeletal motorprotein in the cardiac muscle cell. It is directly responsible forconverting chemical energy into the mechanical force, resulting incardiac muscle contraction.

Current positive inotropic agents, such as beta-adrenergic receptoragonists or inhibitors of phosphodiesterase activity, increase theconcentration of intracellular calcium, thereby increasing cardiacsarcomere contractility. However, the increase in calcium levelsincrease the velocity of cardiac muscle contraction and shortenssystolic ejection time, which has been linked to potentiallylife-threatening side effects. In contrast, cardiac muscle myosinactivators work by a mechanism that directly stimulates the activity ofthe cardiac muscle myosin motor protein, without increasing theintracellular calcium concentration. They accelerate the rate-limitingstep of the myosin enzymatic cycle and shift it in favor of theforce-producing state. Rather than increasing the velocity of cardiaccontraction, this mechanism instead lengthens the systolic ejectiontime, which results in increased cardiac muscle contractility andcardiac output in a potentially more oxygen-efficient manner.

U.S. Pat. No. 7,507,735, herein incorporated by reference, discloses agenus of compounds, including omecamtiv mecarbil (AMG 423, CK-1827452),having the structure:

Omecamtiv mecarbil is a first in class direct activator of cardiacmyosin, the motor protein that causes cardiac contraction. It is beingevaluated as a potential treatment of heart failure in both intravenousand oral formulations with the goal of establishing a new continuum ofcare for patients in both the in-hospital and outpatient settings.

Clinical trials providing an I.V. delivery of omecamtiv mecarbil haveshown that plasma levels of the drug can be delivered safely andeffectively. However, standard release formulations and some extendedrelease formulations gave peak to trough ratios that may be too great toprovide a safe and effective amount of omecamtiv mecarbil to patientswho need the drug in a chronic or preventative setting (See, FIG. 4).Accordingly, an effective sustained release formulation would bedesirable for increased patient safety and effectiveness.

SUMMARY

Provided is a pharmaceutical formulation comprising:

omecamtiv mecarbil, or a pharmaceutically acceptable salt, apharmaceutically acceptable hydrate, or a pharmaceutically acceptablehydrate of a pharmaceutically acceptable salt thereof;

a control release agent;

a pH modifying agent; a filler; and

a lubricant.

Also provided is a process for making a pharmaceutical formulationcomprising:

blending a mixture comprising omecamtiv mecarbil, or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable hydrate, or apharmaceutically acceptable hydrate of a pharmaceutically acceptablesalt thereof, a control release agent, a pH modifying agent, and afiller;

lubricating the blended mixture using a lubricant;

granulating the lubricated blend;

lubricating the resultant granulation using the lubricant; and

compressing the lubricated granulation into desired form.

Also provided is a method of treating a disease selected from acuteheart failure and chronic heart failure, comprising administering apharmaceutical formulation described herein to a patient in needthereof.

DESCRIPTION OF THE FIGURES

FIG. 1 is a flow diagram for the preparation of immediate release (IR)tablets of omecamtiv mecarbil (25 mg); see Example 1.

FIG. 2 is a flow diagram for the preparation of matrix modified releasecompositions; see Example 2.

FIG. 3 is a flow diagram for the preparation of matrix modified releasecompositions; see, Examples 3-5.

FIG. 4 shows the exposure of healthy volunteers (plasma concentration(ng/ml) v. time (h)), fasted (top) and fed (bottom) for an immediaterelease composition (IR) and two matrix modified release compositions(MTX-F1 and MTX-F2).

FIG. 5 is a table with data for an immediate release composition (IR)and two matrix modified release compositions (MTX-F1 and MTX-F2).

FIG. 6 shows drug release at two pHs (2 and 6.8) for a matrixformulation of omecamtiv mecarbil free base (top) and for a omecamtivmecarbil dihydrochloride hydrate salt form, Form A (bottom).

FIG. 7 shows an X-ray powder diffraction pattern (XRPD) for Form A.

FIG. 8 shows an XRPD of a omecamtiv mecarbil dihydrochloride hydratesalt form at varying relative humidity conditions.

FIG. 9 shows an XRPD of a omecamtiv mecarbil dihydrochloride hydratesalt form at varying temperatures.

FIG. 10 shows an overlay of XRPD patterns for Forms A, B and C ofomecamtiv mecarbil dihydrochloride salt.

DETAILED DESCRIPTION

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“Treatment” or “treating” means any treatment of a disease in a patient,including: a) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop; b) inhibiting the disease; c)slowing or arresting the development of clinical symptoms; and/or d)relieving the disease, that is, causing the regression of clinicalsymptoms. Treatment of diseases and disorders herein is intended to alsoinclude the prophylactic administration of a pharmaceutical formulationdescribed herein to a subject (i.e., an animal, preferably a mammal,most preferably a human) believed to be in need of preventativetreatment, such as, for example, chronic heart failure.

The term “therapeutically effective amount” means an amount effective,when administered to a human or non-human patient, to treat a disease,e.g., a therapeutically effective amount may be an amount sufficient totreat a disease or disorder responsive to myosin activation. Thetherapeutically effective amount may be ascertained experimentally, forexample by assaying blood concentration of the chemical entity, ortheoretically, by calculating bioavailability.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate (i.e., hydrochloride),phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, andlike salts; as well as salts with an organic acid, such as malate,maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium. Those skilled in the art will recognizevarious synthetic methodologies that may be used to prepare non-toxicpharmaceutically acceptable addition salts.

The term “hydrate” refers to the chemical entity formed by theinteraction of water and a compound, including, for example, hemi-hydrates, monohydrates, dihydrates, trihydrates, etc.

“Crystalline form,” “polymorph,” and “novel form” may be usedinterchangeably herein, and are meant to include all crystalline andamorphous forms of the compound, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms, as well asmixtures thereof, unless a particular crystalline or amorphous form isreferred to.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

Provided is a pharmaceutical formulation comprising omecamtiv mecarbil,or a pharmaceutically acceptable salt, a pharmaceutically acceptablehydrate, or a pharmaceutically acceptable hydrate of a pharmaceuticallyacceptable salt thereof, such as omecamtiv mecarbil dihydochloridehydrate.

The pharmaceutical formulations described herein are capable ofreleasing omecamtiv mecarbil evenly at a pace controlled by thediffusion of omecamtiv mecarbil through a gel layer formed by thehydration of the control release agents in the tablets. In someembodiments, in conjunction with other above or below embodiments, thepresent modified release matrix tablets demonstrate a minimalpH-dependent release in-vitro. In some embodiments, in conjunction withother above or below embodiments, complete release of omecamtiv mecarbilis achieved in both pH 2 and 6.8 dissolution medium within 24 hours,possibly resulting in less inter- and intra-subject variability and foodeffect. It is found that the present modified release matrix tabletdosage form is superior to the former immediate release dosage form inminimizing the plasma peak-trough ratio. As a result, the presentmodified release matrix tablets reduce plasma concentration fluctuation,leading to reduced side effects, and improved safety and efficacy. It isalso expected that the present modified release matrix tablets willimprove patient compliance by reducing the dosing frequency.Additionally, the present modified release matrix tablets arephysicochemically stable—resulting in no physical attribute, assay,impurity, or dissolution profile changes after storage at 40° C./75% RHfor 6 months.

In some embodiments, in conjunction with other above or belowembodiments, the exposure of omecamtiv mecarbil from two to twelve hoursafter dosing in humans is between 40 and 70 ng/ml.

In some embodiments, in conjunction with other above or belowembodiments, the exposure of omecamtiv mecarbilfrom two to twelve hoursafter dosing in humans remains between 40 and 55 ng/ml.

In some embodiments, in conjunction with other above or belowembodiments, the omecamtiv mecarbil is released in the followingintervals:

≤30% dose dissolved at 1 hour;

30-75% dose dissolved at 3 hours; and

≥80% dose dissolved at 12 hours.

In some embodiments, in conjunction with other above or belowembodiments, the omecamtiv mecarbil is released in the followingintervals:

≤30% dose dissolved at 2 hours;

30-75% dose dissolved at 6 hours; and

≥80% dose dissolved at 16 hours.

Provided is a pharmaceutical formulation comprising:

omecamtiv mecarbil, or a pharmaceutically acceptable salt, apharmaceutically acceptable hydrate, or a pharmaceutically acceptablehydrate of a pharmaceutically acceptable salt thereof;

a control release agent;

a pH modifying agent;

a filler; and

a lubricant.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about

3-30% w/w of omecamtiv mecarbil, or a pharmaceutically acceptable salt,a pharmaceutically acceptable hydrate, or a pharmaceutically acceptablehydrate of a pharmaceutically acceptable salt thereof;

15-35% w/w control release agent;

20-45% w/w pH modifying agent;

25-65% w/w filler; and

0.1-1.0% w/w lubricant.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about

12-25 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 25-35 (w/w %) Methocel™K100 M Prem CR; 20-30 (w/w %) microcrystalline cellulose, PH 102; 5-10(w/w %) lactose monohydrate, FF 316; 12-25 (w/w %) fumaric acid; 0.1-2(w/w %) intra-granular magnesium stearate; and 0.1-2 (w/w %)extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

3-10 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 20-40 (w/w %) Methocel™K100 M Prem CR; 30-42 (w/w %) microcrystalline cellulose, PH 102; 12-25(w/w %) lactose monohydrate, FF 316; 4-11 (w/w %) fumaric acid; 0.1-2(w/w %) intra-granular magnesium stearate; and 0.1-2 (w/w %)extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

12-25 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 1-10 (w/w %) Methocel™K100 M Prem CR; 12-27 (w/w %) Methocel™ K100 LV Prem CR; 20-35 (w/w %)microcrystalline cellulose, PH 102; 4-15 (w/w %) lactose monohydrate, FF316; 12-25 (w/w %) fumaric acid; 0.1-2 (w/w %) intra-granular magnesiumstearate; and 0.1-2 (w/w %) extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

3-10 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 1-10 (w/w %) Methocel™K100 M Prem CR; 12-27 (w/w %) Methocel™ K100 LV Prem CR; 30-50 (w/w %)microcrystalline cellulose, PH 102; 15-25 (w/w %) lactose monohydrate,FF 316; 3-11 (w/w %) fumaric acid; 0.1-2 (w/w %) intra-granularmagnesium stearate; and 0.1-2 (w/w %) extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

18-19 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 28-32 (w/w %) Methocel™K100 M Prem CR; 23-26 (w/w %) microcrystalline cellulose, PH 102; 7-9(w/w %) lactose monohydrate, FF 316; 17-20 (w/w %) fumaric acid; 0.1-1(w/w %) intra-granular magnesium stearate; and 0.1-1 (w/w %)extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

5-7 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 27-33 (w/w %) Methocel™K100 M Prem CR; 35-38 (w/w %) microcrystalline cellulose, PH 102; 17-20(w/w %) lactose monohydrate, FF 316; 6-9 (w/w %) fumaric acid; 0.1-1(w/w %) intra-granular magnesium stearate; and 0.1-1 (w/w %)extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

17-20 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 3-7 (w/w %) Methocel™K100 M Prem CR; 18-22 (w/w %) Methocel™ K100 LV Prem CR; 26-30 (w/w %)microcrystalline cellulose, PH 102; 8-11 (w/w %) lactose monohydrate, FF316; 17-20 (w/w %) fumaric acid; 0.1-1 (w/w %) intra-granular magnesiumstearate; and 0.1-1 (w/w %) extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

5-7 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 3-7 (w/w %) Methocel™K100 M Prem CR; 18-22 (w/w %) Methocel™ K100 LV Prem CR; 37-43 (w/w %)microcrystalline cellulose, PH 102; 18-22 (w/w %) lactose monohydrate,FF 316; 6-9 (w/w %) fumaric acid; 0.1-1 (w/w %) intra-granular magnesiumstearate; and 0.1-1 (w/w %) extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

18.37 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 30 (w/w %) Methocel™K100 M Prem CR; 24.20 (w/w %) microcrystalline cellulose, PH 102; 8.07(w/w %) lactose monohydrate, FF 316; 18.37 (w/w %) fumaric acid; 0.5(w/w %) intra-granular magnesium stearate; and 0.5 (w/w %)extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

6.13 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 30 (w/w %) Methocel™K100 M Prem CR; 36.81 (w/w %) microcrystalline cellulose, PH 102; 18.40(w/w %) lactose monohydrate, FF 316; 7.66 (w/w %) fumaric acid; 0.5 (w/w%) intra-granular magnesium stearate; and 0.5 (w/w %) extra-granularmagnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

18.37 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 5 (w/w %) Methocel™K100 M Prem CR; 20 (w/w %) Methocel™ K100 LV Prem CR; 27.95 (w/w %)microcrystalline cellulose, PH 102; 9.31 (w/w %) lactose monohydrate, FF316; 18.37 (w/w %) fumaric acid; 0.5 (w/w %) intra-granular magnesiumstearate; and 0.5 (w/w %) extra-granular magnesium stearate.

In some embodiments, in conjunction with other above or belowembodiments, the pharmaceutical formulation comprises about:

6.13 (w/w %) omecamtiv mecarbil Di-HCl hydrate; 5 (w/w %) Methocel™ K100M Prem CR; 20 (w/w %) Methocel™ K100 LV Prem CR; 40.14 (w/w %)microcrystalline cellulose, PH 102; 20.07 (w/w %) lactose monohydrate,FF 316; 7.66 (w/w %) fumaric acid; 0.5 (w/w %) intra-granular magnesiumstearate; and 0.5 (w/w %) extra-granular magnesium stearate.

Omecamtiv Mecarbil

In some embodiments, in conjunction with other above or belowembodiments, the drug formulation comprises omecamtiv mecarbildihydrochloride salt. In some embodiments, in conjunction with otherabove or below embodiments, the drug formulation comprises omecamtivmecarbil dihydrochloride hydrate. In some embodiments, in conjunctionwith other above or below embodiments, the drug formulation comprisesomecamtiv mecarbil dihydrochloride hydrate Form A.

In some embodiments, in conjunction with other above or belowembodiments, Form A can be characterized by an X-ray powder diffractionpattern, obtained as set forth in the Examples, having peaks at about6.6, 14.9, 20.1, 21.4, and 26.8±0.2° 2θ using Cu Kα radiation. Form Aoptionally can be further characterized by an X-ray powder diffractionpattern having additional peaks at about 8.4, 24.2, 26.0, 33.3±0.2° 2θusing Cu Kα radiation. Form A optionally can be even furthercharacterized by an X-ray powder diffraction pattern having additionalpeaks at about 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9, 18.9, 19.5, 20.7,21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9,33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7±0.2° 2θ using Cu Kαradiation. In various cases, Form A can be characterized by an XRPDpattern having peaks at about 6.2, 6.6, 8.4, 9.7, 13.2, 14.3, 14.9,15.4, 16.3, 16.9, 18.9, 19.5, 20.1, 20.7, 21.4, 21.8, 22.8, 23.6, 24.3,25.1, 26.0, 26.8, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.3,33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7±0.2° 2θ using Cu Kαradiation. In some embodiments, in conjunction with other above or belowembodiments, Form A can be characterized by an X-ray powder diffractionpattern substantially as depicted in FIG. 7. It is well known in thefield of XRPD that while relative peak heights in spectra are dependenton a number of factors, such as sample preparation and instrumentgeometry, peak positions are relatively insensitive to experimentaldetails.

Form B and Form C polymorphs of omecamtiv mecarbil, are metastableanhydrous dihydrochloride forms, and can be formed under variedhydration conditions and temperatures, as noted in FIGS. 8 and 9.Characteristic Form B 2-theta values include 6.8, 8.8, 14.7, 17.7, and22.3±0.2° 2θ using Cu Kα radiation, and can additionally include peaksat 9.6, 13.5, 19.2, 26.2±0.2° 2θ using Cu Kα radiation. Form B can becharacterized with XRPD pattern peaks at 6.2, 6.8, 8.8, 9.6, 13.5, 14.4,14.7, 15.4, 16.3, 17.0, 17.7, 18.3, 19.2, 19.9, 20.5, 20.8, 21.8, 22.3,22.7, 23.0, 24.8, 25.1, 25.5, 26.2, 26.4, 26.8, 27.5, 28.5, 30.2, 30.6,31.1, 31.5, 32.1, 32.7, 34.1, 34.4, 35.5, 35.9, 38.1, 38.9±0.2° 2θ usingCu Kα radiation. Characteristic Form C 2-theta values include 6.7, 14.8,17.4, 20.6, and 26.2±0.2° 2θ using Cu Kα radiation, and can additionallyinclude peaks at 8.7, 22.0, 27.1, and 27.7±0.2° 2θ using Cu Kαradiation. Form C can be characterized with XRPD pattern peaks at 6.2,6.7, 8.7, 9.6, 13.5, 14.5, 14.8, 15.4, 16.4, 17.1, 17.4, 18.4, 19.3,19.5, 19.9, 20.6, 20.8, 21.8, 22.0, 22.5, 22.8, 24.3, 24.7, 25.1, 25.6,26.2, 26.5, 27.1, 27.3, 27.7, 28.5, 30.0, 30.5, 31.0, 31.5, 32.2, 32.8,34.1, 35.2, 36.0, 36.9, and 38.8±0.2° 2θ using Cu Kα radiation.

See, also, FIG. 9 (variable temperature XRPD data), FIG. 8 (variablerelative humidity XRPD data), and FIG. 10 (overlay)

Control Release Agent

As used herein, the term “control release agents” refer to agents thatfacilitate the release of the active ingredient from the presentcomposition in a controlled fashion. In some embodiments, in conjunctionwith other above or below embodiments, the control release agents form agel upon hydration. Control release agents include pulluan, dextrin,sodium and calcium acid, polyacrylic acid, polymethacrylic acid,polymethylvinylether co-maleic anhydride, polyvinylpyrrolidone,polyethylene oxide, polyethylene glycol, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylmethacrylate, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, methylcellulose, maltodextrin, xanthan gum,tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins,pre-gelatinized starch, polyvinyl alcohol, carboxymethylethylcellulose,cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthate, hydroxymethylethylcellulosephthate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, polyvinyl alcohol phthalate, polyvinyl butylatephthalate, polyvinyl acetal phthalate, a copolymer of vinylacetate/maleic anhydride, a copolymer of styrene/maleic acid monoester,a copolymer of methyl acryl-ate/methacrylic acid, a copolymer ofstyrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methylmethacrylate, benzylaminomethylcellulose, diethylaminomethylcellulose,piperidylethylhydroxyethylcellulose, cellulose acetatedimethylaminoacetate, a copolymer of vinyl diethylamine/vinyl acetate, acopolymer of vinyl benzylamine/vinyl acetate, polyvinylacetaldiethylamino acetate, a copolymer ofvinylpiperidylacetoacetal/vinyl acetate, polydiethylaminomethylstyrene,a copolymer of methyl methacrylate/butyl methacrylate/dimethylaminoethylmethacrylate and polydimethylaminoethylmethacrylate, a copolymer of2-methyl-5-vinylpyridine/methylmethacrylate/methacrylic acid, acopolymer of 2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid,a copolymer of 2-vinyl-5-ethylpyridine/methacrylic acid/methy acrylate,a copolymer of 2-vinylpyrid-ine/methacrylic acid/acrylonitrile,carboxymethylpiperidyl starch, carboxy-methylbenzylaminocellulose, acopolymer of N-vinylglycine/styrene, chitosan, poly(vinyl alcohol),maleic anhydride copolymer, poly (vinyl pyrolidone), starch andstarch-based polymers, poly (2-ehtyl-2-oxazoline), poly(ethyleneimine),polyurethane hydrogels, welan gum, rhamsan gum, polyvinyl acetates,ethylcellulose, eudragit RL, RS, NE 30D, Kollicoat EMM 30D, orcombinations thereof.

In some embodiments, in conjunction with other above or belowembodiments, the control release agent is a polymer.

In some embodiments, in conjunction with other above or belowembodiments, the control release agent is selected from pulluan,dextrin, sodium and calcium acid, polyacrylic acid, polymethacrylicacid, polymethylvinylether co-maleic anhydride, polyvinylpyrrolidone,polyethylene oxide, polyethylene glycol, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxymethylmethacrylate, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, methylcellulose, maltodextrin, xanthan gum,tragacanth gum, agar, gellan gum, kayara gum, alginic acids, pectins,pre-gelatinized starch, polyvinyl alcohol, carboxymethylethylcellulose,cellulose acetate phthalate, cellulose acetate succinate,methylcellulose phthate, hydroxymethylethylcellulosephthate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, polyvinyl alcohol phthalate, polyvinyl butylatephthalate, polyvinyl acetal phthalate, a copolymer of vinylacetate/maleic anhydride, a copolymer of styrene/maleic acid monoester,a copolymer of methyl acryl-ate/methacrylic acid, a copolymer ofstyrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methylmethacrylate, benzylaminomethylcellulose, diethylaminomethylcellulose,piperidylethylhydroxyethylcellulose, cellulose acetatedimethylaminoacetate, a copolymer of vinyl diethylamine/vinyl acetate, acopolymer of vinyl benzylamine/vinyl acetate, polyvinylacetaldiethylamino acetate, a copolymer ofvinylpiperidylacetoacetal/vinyl acetate, polydiethylaminomethylstyrene,a copolymer of methyl methacrylate/butyl methacrylate/dimethylaminoethylmethacrylate and polydimethylaminoethyl methacrylate, a copolymer of2-methy-5vinylpyrid¬dne/methylmethacry¬tate/methacrylic acid, acopolymer of 2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid,a copolymer of 2-vinyl-5-ethylpyridine/methacrylic acid/methy acrylate,a copolymer of 2-vinylpyrid-ine/methacrylic acid/acrylonitrile,carboxymethylpiperidyl starch, carboxy-methylbenzylaminocellulose, acopolymer of N-vinylglycine/styrene, chitosan, poly(vinyl alcohol),maleic anhydride copolymer, poly (vinyl pyrolidone), starch andstarch-based polymers, poly (2-ehtyl-2-oxazoline), poly(ethyleneimine),polyurethane hydrogels, welan gum, rhamsan gum, polyvinyl acetates,ethylcellulose, eudragit RL, RS, NE 30D, and Kollicoat EMM 30D, or anycombination thereof.

pH Modifying Agent

As used herein, the term “pH modifying agent” refers to an agent capableof modulating the pH to a desired range. In some embodiments, inconjunction with other above or below embodiments, the pH modifyingagent is an acidifying agent. In some embodiments, in conjunction withother above or below embodiments, the pH modifying agent is present inan amount sufficient to lower the pH. pH Modulation agents includemaleic acid, citric acid, tartaric acid, pamoic acid, fumaric acid,salicylic acid, 2,6-diaminohexanoic acid, camphorsulfonic acid,glycerophosphoric acid, 2-hydroxyethanesulfonic acid, isethionic acid,succinic acid, carbonic acid, p-toluenesulfonic acid, aspartic acid,8-chloro¬theophylline, benezenesulfonic acid, malic acid, orotic acid,oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearic acid,adipic acid, p-amino¬salicylic acid, 5-aminoslicylic acid, ascorbicacid, sulfuric acid, cyclamic acid, sodium lauryl sulfate, glucoheptonicacid, glucuronic acid, glycine, sulfuric acid, mandelic acid,1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid,2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid,p-acetamidobenzoic acid, o-acetamido-benzoic acid, m-acetamidobenzoicacid, N-acetyl-L-aspartic acid, camphoric acid, dehydrocholic acid,malonic acid, edetic acid, ethylenediainetetraacetic acid, ethylsulfuricacid, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizicacid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid,4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoicacid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3′-adenylic acid,5′-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pecticacid, polygalacturonic acid, 5-sulfosalicylic acid,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid,terephthalic acid, 1-hydroxy-2naphthoic acid, and combinations thereof.In some embodiments, in conjunction with other above or belowembodiments, acidic excipients include, for example, maleic acid, citricacid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactoicacid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid,glutamic acid, and combinations thereof.

In some embodiments, in conjunction with other above or belowembodiments, pH modifying agent includes maleic acid, citric acid,tartaric acid, pamoic acid, fumaric acid, salicylic acid,2,6-diaminohexanoic acid, camphorsulfonic acid, glycerophosphoric acid,2-hydroxyethanesulfonic acid, isethionic acid, succinic acid, carbonicacid, p-toluenesulfonic acid, aspartic acid, 8-chlorotheophylline,benezenesulfonic acid, malic acid, orotic acid, oxalic acid, benzoicacid, 2-naphthalenesulfonic acid, stearic acid, adipic acid,p-amino-salicylic acid, 5-aminoslicylic acid, ascorbic acid, sulfuricacid, cyclamic acid, sodium lauryl sulfate, glucoheptonic acid,glucuronic acid, glycine, sulfuric acid, mandelic acid,1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid,2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid,p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoicacid, N-acetyl-L-aspartic acid, camphoric acid, dehydrocholic acid,malonic acid, edetic acid, ethylenediainetetraacetic acid, ethylsulfuricacid, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizicacid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid,4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoicacid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3′-adenylic acid,5′-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pecticacid, polygalacturonic acid, 5-sulfosalicylic acid,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid,terephthalic acid, 1-hydroxy-2naphthoic acid, and combinations thereof.

In some embodiments, in conjunction with other above or belowembodiments, the pH modifying agent is selected from maleic acid, citricacid, malic acid, fumaric acid, sulfuric acid, tartaric acid, lactoicacid, salicylic acid, aspartic acid, aminosalicylic acid, malonic acid,glutamic acid, and any combination thereof.

In some embodiments, in conjunction with other above or belowembodiments, fumaric acid was used as the pH modifying agent as it isless hygroscopic and more compatible with omecamtiv mecarbildihydrochloride hydrate than citric acid, resulting in less or no activeform transformation and no changes in tablet appearance when stored at40° C./75% RH for 6 months, leading to improved final product quality.Additionally, fumaric acid is more acidic (2-fold) than citric acid.Therefore, it is more efficient, i.e., 1:1 weight ratio to activeinstead of 2:1, to use fumaric acid to modulate the microenvironmentalpH to enhance omecamtiv mecarbil release at neutral environment. Fumaricacid also has a very slow dissolution rate. As a result, fumaric acidwill stay in the tablet longer and maintain the low micro-environmentalpH better, resulting in more complete release of omecamtiv mecarbilwithin 24 hours.

Filler

As used herein, the term “fillers” refers to one or more substances thatcan be added to components of a pharmaceutical composition to increasebulk weight of the material to be formulated, e.g. tableted, in order toachieve the desired weight. Fillers include but are not limited tostarches, lactose, mannitol (such as Pearlitol™ SD 200), cellulosederivatives, calcium phosphate, sugar and the like.

Different grades of lactose include, but are not limited, to lactosemonohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™(available from Meggle products), Pharmatose™ (available from DMV) andothers. Different grades of starches include, but are not limited to,maize starch, potato starch, rice starch, wheat starch, pregelatinizedstarch (commercially available as PCS PC10 from Signet ChemicalCorporation) and Starch 1500, Starch 1500 LM grade (low moisture contentgrade) from Colorcon, fully pregelatinized starch (commerciallyavailable as National 78-1551 from Essex Grain Products) and others.Different cellulose compounds that can be used include crystallinecellulose and powdered cellulose. Examples of crystalline celluloseproducts include but are not limited to CEOLUS™ KG801, Avicel™ PH 101,PH102, PH301, PH302 and PH-F20, microcrystalline cellulose 114, andmicrocrystalline cellulose 112. Other useful fillers include, but arenot limited to, carmellose, sugar alcohols such as mannitol, sorbitoland xylitol, calcium carbonate, magnesium carbonate, dibasic calciumphosphate, and tribasic calcium phosphate.

In some embodiments, in conjunction with other above or belowembodiments, the filler is selected from starch, lactose, mannitol (suchas Pearlitol™ SD 200), cellulose derivatives, calcium phosphate, and asugar.

In some embodiments, in conjunction with other above or belowembodiments, the filler is lactose anhydrous or lactose monohydrate. Insome embodiments, in conjunction with other above or below embodiments,the filler is lactose DT, Flowlac™, or Pharmatose™.

In some embodiments, in conjunction with other above or belowembodiments, the filler is maize starch, potato starch, rice starch,wheat starch, pregelatinized starch (such as Starch 1500 or Starch 1500LM grade (low moisture content grade)), or fully pregelatinized starch.

In some embodiments, in conjunction with other above or belowembodiments, the filler is microcrystalline cellulose, such as CEOLUS™KG801, Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, microcrystallinecellulose 114, or microcrystalline cellulose 112.

In In some embodiments, in conjunction with other above or belowembodiments, the filler is carmellose, mannitol, sorbitol, xylitol,calcium carbonate, magnesium carbonate, dibasic calcium phosphate, ortribasic calcium phosphate.

Lubricant

As used herein, the term “lubricants” refers to one or more substancesthat can be added to components of the present compositions to reducesticking by a solid formulation to the equipment used for production ofa unit doss form. Lubricants include stearic acid, hydrogenatedvegetable oils, hydrogenated soybean oil and hydrogenated soybean oil &castor wax, stearyl alcohol, leucine, polyethylene glycol, magnesiumstearate, glycerylmonostearate, stearic acid, glycerybehenate,polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate,magnesium lauryl sulfate, sodium oleate, sodium stearylFumarate,DL-leucine, colloidal silica, and mixtures thereof.

In some embodiments, in conjunction with other above or belowembodiments, the lubricant is stearic acid, hydrogenated vegetable oil,hydrogenated soybean oil, hydrogenated soybean oil, castor wax, stearylalcohol, leucine, polyethylene glycol, magnesium stearate,glycerylmonostearate, stearic acid, glycerybehenate, polyethyleneglycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium laurylsulfate, sodium oleate, sodium stearylfumarate, DL-leucine, colloidalsilica, or any mixture thereof.

Manufacturing Process

Also provided is a process for making a pharmaceutical formulationdescribed herein, comprising:

blending a mixture comprising omecamtiv mecarbil, or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable hydrate, or apharmaceutically acceptable hydrate of a pharmaceutically acceptablesalt thereof, a control release agent, a pH modifying agent, and afiller;

lubricating the blended mixture using a lubricant;

granulating the lubricated blend;

lubricating the resultant granulation using the lubricant; and

compressing the lubricated granulation into desired form.

Also provided is a process for making a pharmaceutical formulationdescribed herein, comprising:

providing a blended mixture comprising omecamtiv mecarbil, or apharmaceutically acceptable salt, a pharmaceutically acceptable hydrate,or a pharmaceutically acceptable hydrate of a pharmaceuticallyacceptable salt thereof, a control release agent, a pH modifying agent,a filler, and a lubricant;

granulating the blended mixture; and

compressing the lubricated granulation into desired form.

Also provided is a process for making a pharmaceutical formulationdescribed herein, comprising:

compressing a granulation of omecamtiv mecarbil, or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable hydrate, or apharmaceutically acceptable hydrate of a pharmaceutically acceptablesalt thereof, a control release agent, a pH modifying agent, a filler,and a lubricant into desired form.

In some embodiments, in conjunction with other above or belowembodiments, the modified release matrix tablets are manufactured usingdry granulation. The dry granulation process can help to avoid theactive form transformation in the modified release matrix tablets. Inaddition, dry granulation process avoids issues observed in a high shearwet granulation process.

Also provided is a pharmaceutical formulation prepared by any of theprocesses described herein.

Stability

Forced degradation conditions (e.g., 40° C. and 75% relative humidity)are used to evaluate the long-term storage stability of a pharmaceuticalingredient or composition. In general terms, a stable composition is onewhich, after being subjected to forced degradation conditions, comprisesthe pharmaceutically active ingredients in an amount, for example 95%,relative to the amount initially present in the particular composition.Stability may be determined, using forced degradation or other methods,for periods of 1 week, 1 month, 2 months, 3 months, 4 months, 5 months,6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30months, 36 months, longer.

Assays for evaluating the stability of a pharmaceutical composition,such as those described herein, are known in the pharmaceutical arts.For example, one can determine the percentage of active pharmaceuticalingredients present in a given composition, as well as the presence andpercentage of impurities, through the use of standard analyticaltechniques.

Methods of Treatment/Use of Formulations Disclosed

Also provided is a method for the use of such pharmaceuticalformulations for the treatment of heart failure, including but notlimited to: acute (or decompensated) congestive heart failure, andchronic congestive heart failure; particularly diseases associated withsystolic heart dysfunction.

EXAMPLES Manufacture of Omecamtiv Mecarbil Dihydrochloride HydrateSynthetic Route to Omecamtiv Mecarbil

Synthesis of the API SM Piperazine Nitro-HCl

General Methods

Reagents and solvents were used as received from commercial sources. ¹HNMR spectra were recorded on a 400 MHz spectrometer. Chemical shifts arereported in ppm from tetramethylsilane with the solvent resonance as theinternal standard (CDCl₃, DMSO-d₆). Data are reported as follows:chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,q=quartet, br=broad, m=multiplet), coupling constants (Hz) andintegration. ¹³C NMR spectra were recorded on a 100 MHz spectrometerwith complete proton decoupling. Chemical shifts are reported in ppmfrom tetramethylsilane with the solvent as the internal reference(CDCl₃, DMSO-d₆). All solvent charges are made with respect to starting2-Fluoro-3-nitrotoluene.

X-Ray powder diffraction data (XRPD) were obtained using aPANalyticalX′Pert PRO diffractometer (PANalytical, Almelo, TheNetherlands) fitted with a real time multiple strip (RTMS) detector. Theradiation used was CuKα (1.54 Å) and the voltage and current were set at45 kV and 40 mA, respectively. Data were collected at room temperaturefrom 5 to 45 degrees 2-theta with a step size of 0.0334 degrees. Sampleswere prepared on a low background sample holder and placed on the samplestage which was rotated with a 2 second revolution time.

Alternatively, XRPD data were obtained using a PANalyticalX′Pert PROdiffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMSdetector. The radiation used was CuKα (1.54 Å) and the voltage andcurrent were set at 45 kV and 40 mA, respectively. Data were collectedat room temperature from 5 to 40, degrees 2-theta with a step size of0.0334 degrees. Samples were prepared on a low background sample holderand placed on the sample stage which was rotated with a 2 secondrevolution time.

Alternatively, XRPD data were obtained using a PANalyticalX′Pert PROdiffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMSdetector. The radiation used was CuKα (1.54 Å) and the voltage andcurrent were set at 45 kV and 40 mA, respectively. Data were collectedat room temperature from 5 to 40, degrees 2-theta with a step size of0.0167 degrees. Samples were prepared on a low background sample holderand placed on the sample stage which was rotated with a 2 secondrevolution time.

Alternatively, XRPD data were obtained using a PANalyticalX′Pert Prodiffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMSdetector. The radiation used was CuKα (1.54 Å) and the voltage andcurrent were set at 45 kV and 40 mA, respectively. Data were collectedat room temperature from 3 to 40, degrees 2-theta with a step size of0.008 degrees. Samples were prepared on a low background sample holderand placed on the sample stage with a 2 second revolution time.

Alternatively, XRPD data were obtained using a Bruker D8 Discover X-raydiffraction system (Bruker, Billerica, Mass.) fitted with a motorizedxyz sample stage and a GADDS area detector. The radiation used was CuKα(1.54 Å) and the voltage and current were set at 45 kV and 40 mA,respectively. The solid samples on a flat glass plate were mapped andfor each sample an area of 1 mm² was scanned in an oscillating mode for3 minutes from 5 to 48 degrees 2-theta.

Differential Scanning calorimetry (DSC) data was collected usingstandard DSC mode (DSC Q200, TA Instruments, New Castle, Del.). Aheating rate of 10° C./min was employed over a temperature range from40° C. to 300° C. Analysis was run under nitrogen and samples wereloaded in standard, hermetically-sealed aluminum pans. Indium was usedas a calibration standard.

Alternatively, DSC data were collected using temperature-modulated DSCmode (DSC Q200, TA Instruments, New Castle, Del.). After sampleequilibration at 20° C. for five minutes, the heating rate of 3° C./minwas employed with a modulation of +/−0.75° C./min over a temperaturerange from 20° C. to 200° C. Analysis was run under nitrogen and sampleswere loaded in standard, uncrimped aluminum pans. Indium was used as acalibration standard.

FN-Bromide

In a 60 L reactor (containing no exposed Stainless steel, Hastelloy®, orother metal parts) equipped with a reflux/return condenser and scrubbercharged with a 5N NaOH solution, a mechanically stirred mixture ofFN-Toluene (2.0 kg, 12.89 mol, 1.0 equiv.), N-Bromosuccinimide (3.9 kg,21.92 mol, 1.70 equiv.), benzoyl peroxide (125.0 g, 0.03 equiv., 0.39mol, containing 25 wt % water), and acetic acid (7.0 L, 3.5 volumes) washeated to 85° C. under an atmosphere of nitrogen for 7 hours. A solutionof H₃PO₃ (106.0 g, 1.29 mol, 0.1 equiv.) and acetic acid (200 mL, 0.1volume), prepared in separate vessel, was added. The reaction mixturewas agitated for 0.5 h and analysis of an aliquot confirmed completedecomposition of benzoyl peroxide (not detected, HPLC_(254 nm)). Thereaction mixture was cooled to 22° C. DI Water (8.0 L, 4 volumes) andtoluene (16.0 L, 8 volumes) were charged, the biphasic mixture wasagitated (20 min), and the layers were separated. Aqueous 1.6N NaOH(14.0 L, 7.0 volumes) was added to the organic layer at a rate allowingthe batch temperature to stay under 25° C. and the pH of the resultantaqueous phase was measured (≥11). The biphasic mixture was filteredthrough a 5 μm Teflon® cartridge line and the layers were separated. Thefilter line was washed with another 2 L of toluene.

The assay yields were 2.5% of FN-Toluene, 62.3% of FN-Bromide and 30.0%of Di-Bromide. The toluene solution contained no benzoyl peroxide,succinimide, or α-bromoacetic acid and water content by KF titration was1030 ppm (This solution could be held under nitrogen at room temperaturefor >12 h without any change in the assay yield).

To this solution at room temperature was added diisopropylethylamine(880.0 g, 6.63 mol, 0.53 equiv.) followed by methanol (460 mL, 11.28mol, 0.88 equiv.) and heated to 40° C. A solution of diethylphosphite(820.0 g, 5.63 mol, 0.46 equiv.) in methanol (460 mL, 11.28 mol, 0.88equiv.) was prepared and added to the reaction mixture at 40° C. throughan addition funnel over a period of 1 hour at such a rate that the batchtemperature was within 40±5° C. The contents were stirred for a periodof 3 h at 40° C. from the start of addition and cooled to roomtemperature and held under nitrogen atmosphere for 12 hours. The assayyield of the reaction mixture was 2.5% FN-Toluene 92.0% FN-Bromide and0.2% Di-Bromide. This solution is used as such for the alkylation step.

Characterization for components of final product mixture (collected forpure compounds).

2-Fluoro-3-Nitrotoluene (FN-Toluene): ¹H NMR (400 MHz, CHLOROFORM-d) δppm 2.37 (s, 1H), 7.13-7.20 (m, 1H), 7.45-7.51 (m, 1H), 7.79-7.85 (m,1H). ¹³C NMR (100 MHz, CHLOROFORM-d) δ ppm 14.3 (d, J=5 Hz), 123.3 (d,J=3 Hz), 123.6 (d, J=5 Hz), 128.2 (d, J=16 Hz), 136.7 (d, J=5 Hz), 137.5(broad), 153.7 (d, J=261 Hz); 1-(bromomethyl)-2-fluoro-3-nitrobenzene(FN-Bromide): ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.56 (s, 1H),7.28-7.34 (m, 1H), 7.69-7.76 (m, 1H), 7.98-8.05 (m, 1H). ¹³C NMR (100MHz, CHLOROFORM-d) δ ppm 23.6 (d, J=5 Hz), 124.5 (d, J=5 Hz), 126.1 (d,J=3 Hz), 128.5 (d, J=14 Hz), 136.5 (d, J=4 Hz), 137.7 (broad), 153.3 (d,J=265 Hz). DSC: single melt at 53.59° C. Exact Mass [C₇H₅BrFNO₂+H]⁺:calc.=233.9566, measured=233.9561;1-(dibromomethyl)-2-fluoro-3-nitrobenzene (Dibromide): ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 6.97 (s, 1H), 7.39-7.45 (m, 1H), 8.03-8.10 (m, 1H),8.16-8.21 (m, 1H). ¹³C NMR (100 MHz, CHLOROFORM-d) δ ppm 29.2 (d, J=7Hz), 124.9 (d, J=5 Hz), 127.1 (d, J=2 Hz), 132.1 (d, J=11 Hz), 135.7 (d,J=2 Hz), 137.2 (broad), 149.8 (d, J=266 Hz). DSC: single melt at 49.03°C. Exact Mass [C₇H₄Br₂FNO₂+H]⁺: calc.=311.8671, measured=311.8666.

Piperazine Nitro-HCl:

To a mechanically stirred toluene solution (9 volumes) of FN-Bromide(prepared from previous step) in a 60 L reactor at 22° C. under anatmosphere of nitrogen, diisopropylethylamine was charged (1.90 kg,14.69 mol, 1.14 equiv.). To this mixture a solution of piperazinecarboxylate methylester (Piperazine Carboxylate) (2.03 kg, 14.05 mol,1.09 equiv.) in toluene (1.0 L, 0.5 volumes) was added at a rateallowing the batch temperature to stay under 30.0° C. (Exothermic.During the addition, jacket temperature was adjusted to 5° C. in orderto maintain batch temperature below 30° C. The mixture was agitated at22° C. for 3 hours and analysis of an aliquot confirmed completion ofthe alkylation reaction (<1.0 LCAP FN-Bromide, HPLC_(254 nm)). Thereaction mixture was treated with aqueous NH₄Cl (20 wt %, 10.0 L, 5volumes; prepared from 2.0 kg of NH₄Cl and 10.0 L of DI water), thebiphasic mixture was agitated (30 min), and the layers were separated.The organic layer was sequentially washed with aqueous NaHCO₃ (9 wt %,10.0 L, 5 volumes; prepared from 0.90 kg of NaHCO₃ and 10.0 L of DIwater). The organic layer was filtered through a 5 μm Teflon® cartridgeline and transferred in a drum, washed the filter line with another 1.0L toluene and the combined toluene solution (10.0 volumes) weighed, andassayed (HPLC) to quantify Piperazine Nitro free base. The assay yieldfor the Piperazine Nitro-freebase is 89.0%, FN-Toluene 2.5% andFN-Bromide 0.2% with FN-Bromide undetected. The total loss of product tothe aqueous washes is <1.0%. This solution under nitrogen atmosphere isstable for more than 12 h.

To a mechanically stirred toluene solution of Piperazine Nitro freebase, prepared as described above, at 22° C. in a 60 L reactor under anatmosphere of nitrogen, IPA (19.4 L, 9.7 volumes) and DI water (1.0 L,0.5 volume) were charged. The mixture was heated to 55° C. and 20% ofthe 1.4 equiv. of conc. HCl (Titrated prior to use and charge based ontiter value; 276.0 mL, 3.21 mol) was charged. The contents were agitatedfor 15 min and Piperazine Nitro-HCl seed (130.0 g, 0.39 mol, 0.03equiv.) was charged as slurry in IPA (400 mL, 0.2 volume). The mixturewas agitated for 30 min and the remaining conc. HCl (80% of the charge,1.10 L, 12.82 mol) was added over a period of 4 hours. The mixture wasstirred at 55° C. for 1 h, cooled to 20° C. in a linear manner over 1.5hours, and agitated at this temperature for 12 hours. The supernatantconcentration of Piperazine Nitro-HCl was measured (2.8 mg/g). Themixture was filtered through an aurora filter equipped with a 5 μmTeflon® cloth. The mother liquor were transferred to a clean drum andassayed. The filter cake was washed twice with IPA (11.2 L, 5.6 volumes)and dried to constant weight (defined as ≤1.0% weight loss for 2consecutive TGA measurements over a period of 2 hours) on filter withvacuum and a nitrogen sweep (14 h). The combined losses of PiperazineNitro-HCl in the mother liquors and the washes were 2.5%. PiperazineNitro-HCl was isolated 3.59 kg in 87.6% corrected yield with >99.5 wt %and 99.0% LCAP purity.

Methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride(Piperazine Nitro-HCl): ¹H NMR (300 MHz, DMSO-d) δ ppm 3.25 (br. s, 3H),3.52-3.66 (m, 8H), 4.47 (s, 2H), 7.44-7.63 (t, 1H, J=8 Hz), 7.98-8.15(m, 1H), 8.17-8.34 (m, 1H). ¹³C NMR (75 MHz, DMSO-d) δ ppm 50.3, 51.4,52.8, 119.6 (d, J=14 Hz), 125.1 (d, J=5 Hz), 127.9, 137.4 (d, J=8 Hz),139.8 (d, J=3 Hz), 152.2, 154.7, 155.7. DSC: melt onset at 248.4° C.Exact Mass [C₁₃H₁₆FN₃O₄+H]⁺: calculated=298.1203, measured=298.1198.

Piperazine Nitro Freebase:

In a 60 L reactor equipped with a reflux/return condenser, a mixture ofPiperazine Nitro-HCl (2.0 kg, 5.99 mol, 1.0 equiv.) and isopropylacetate (6.0 L, 3.0 volumes) was mechanically agitated at ambienttemperature under an atmosphere of nitrogen. A solution of sodiumbicarbonate (629 g, 7.49 mol, 1.25 equiv.) and water (7.5 L, 3.75volume), prepared in separate vessel, was added. The biphasic mixturewas agitated (15 min), and the layers were separated. The upper organiclayer (containing product) was transferred to a separate vessel whilethe reactor was rinsed with water and isopropanol. The organic layer wasthen transferred through an inline 5 μm Teflon® cartridge back into theclean 60 L reactor. The filter line was washed with 4.0 L (2.0 volumes)of isopropanol into the 60 L reactor. An additional 12.0 L (6.0 volumes)of isoproponal was added to the 60 L reactor and heated to 40° C. Underreduced pressure (50 torr) the batch was concentrated down toapproximately 6 L (3.0 volumes). The solution was cooled from 27° C. to20° C. in a linear manner over 10 minutes. Water (4.0 L, 2.0 volumes)was added at 20° C. over 30 minutes followed by Piperazine NitroFreebase seed (18 g, 0.06 mol, 0.01 equiv). The mixture was aged for 5minutes and the remaining water (24.0 L, 12.0 volumes) was added over 90minutes. After holding overnight at 20° C., the supernatantconcentration of Piperazine Nitro Freebase was measured (<10 mg/mL). Themixture was filtered through an aurora filter equipped with a 12 μmTeflon® cloth. The filter cake was washed with a mixture of water (3.3L, 1.65 volumes) and isopropanol (700 mL, 0.35 volumes) and dried toconstant weight (defined as 1.0% weight loss for 2 consecutive TGAmeasurements over a period of 2 hours) on filter with vacuum and anitrogen sweep (48 h). The combined losses of Piperazine Nitro Freebasein the mother liquors and the wash were approximately 7.5%. PiperazineNitro Freebase was isolated 1.67 kg in 92.5% corrected yield with 100.0wt % and 99.4% LCAP purity.

Synthesis of the API SM Phenyl Carbamate-HCl

A 60 L, glass-lined, jacketed reactor set at 20° C. under nitrogenatmosphere and vented through a scrubber (containing 5N NaOH) wascharged with 2.5 kg of Amino Pyridine (1.0 equiv, 23.1 moles), followedby 25 L (19.6 kg, 10 vol) acetonitrile. After initiating agitation and(the endothermic) dissolution of the Amino Pyridine, the vessel wascharged with 12.5 L of N-methyl-2-pyrolidinone (12.8 kg, 5 vol). Anaddition funnel was charged with 1.8 L (0.6 equiv, 13.9 moles) phenylchloroformate which was then added over 68 minutes to the solution ofthe Amino Pyridine keeping the internal temperature 30° C. The reactionwas agitated for >30 minutes at an internal temperature of 20±5° C. Thevessel was then charged with 61±1 g of seed as a slurry in 200 mLacetonitrile and aged for 30 min. The addition funnel was charged with1.25 L (0.45 equiv, 9.7 moles) of phenyl chloroformate which was thenadded over 53 minutes to the reaction suspension while again keeping thetemperature ≤30° C. The contents of the reactor were aged 30 hours at20±5° C. After assaying the supernatant 15 mg/g for both product andstarting material), the solids were filtered using an Aurora filterequipped with a 12 μm Teflon cloth. The mother liquor was forwarded to a2^(nd) 60 L, glass-lined, jacketed reactor. The reactor and cake wererinsed with 1×10 L of 5:10 NMP/ACN and 1×10 L ACN. The washes wereforwarded to the 2^(nd) reactor as well. The cake was dried under vacuumwith a nitrogen bleed for 24 hours to afford 5.65 kg (90.2% yield) ofthe product, Phenyl Carbamate-HCl as an off-white solid in 98.8 wt %with 99.2% LCAP purity.

Phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (PhenylCarbamate-HCl) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.24 (s, 1H), 8.81 (s,1H), 8.41 (d, 1H, J=8.8 Hz), 7.85 (d, 1H, J=8.8 Hz), 7.48-7.44 (m, 2H),7.32-7.26 (m, 3H), 2.69 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ ppm151.66, 150.01, 147.51, 136.14, 133.79, 129.99, 129.49, 127.75, 125.87,121.70, 18.55: HR-MS: Calculated for C₁₃H₁₂N₂O₂: 228.0899,M+H⁺=229.0972; Observed mass: 229.0961

GMP Steps

Methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (PiperazineAniline)

To a 100-L jacketed glass-lined reactor were added methyl4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride (2.00kg, 1.00 equiv) and isopropyl acetate (6.00 L, 3.00 Vol with-respect tostarting material). The resulting slurry was agitated under a nitrogensweep. To the mixture was added dropwise over 45±30 min: 7.7% w/waqueous sodium bicarbonate solution (629 g, 1.25 equiv of sodiumbicarbonate dissolved in 7.50 L water), maintaining an internaltemperature of 20±5° C. by jacket control (NOTE: addition isendothermic, and may evolve up to 1 equiv of carbon dioxide gas). Themixture was stirred for 15 min, resulting in a clear biphasic mixture.Agitation was stopped and the layers were allowed to settle.

The bottom (aqueous) layer was drained and analyzed by pH paper toensure that the layer is pH >6. Quantitative HPLC analysis of the upper(organic) layer revealed 97-100% assay yield of the methyl4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate freebase (1.73-1.78kg). The upper (organic) layer was transferred through an in-line filterinto a 20-L Hastelloy® hydrogenator, and the 100-L reactor and lineswere rinsed with an additional aliquot of isopropyl acetate (2.00 L,1.00 Vol). The hydrogenator was purged with nitrogen and vented toatmospheric pressure. To the reaction mixture was added a slurry of 5.0wt % palladium on carbon (20.0 g, Strem/BASF Escat™ 1421, approx 50%water) in isopropyl acetate (400 mL), followed by a 400 mL rinse. Theresulting reaction mixture was diluted with an additional aliquot ofisopropyl acetate (1.2 L; total isopropyl acetate amount is 10.0 L, 5.00Vol). The hydrogenator was purged three times with nitrogen (pressurizedto 60±10 psig, then vented to atmospheric pressure), then pressurized to60±5 psig with hydrogen. The reaction mixture was stirred at <100 rpm at30±5° C. while maintaining 60±5 psig hydrogen, for >2 hours untilreaction was deemed complete. This temperature and pressure correspondto a measured kLa value of approx 0.40 in a 20-L Hydrogenator. End ofreaction is determined by dramatic decrease in hydrogen consumptionaccompanied by a relief in the heat evolution of the reaction. Tocontrol potential dimeric impurities, the reaction is continued for atleast 30 minutes after this change in reaction profile, and HPLCanalysis is performed to confirm that >99.5% conversion of thehydroxyl-amine to the aniline is achieved.

At the end of reaction, the hydrogenator was purged with nitrogen twice(pressurized to 60±10 psig, then vented to atmospheric pressure). Thecrude reaction mixture was filtered through a 5 μm filter followed by a0.45 μm filter in series, into a 40-L glass-lined reactor. Thehydrogenator and lines were washed with an additional aliquot ofisopropyl acetate (2.00 L). Quantitative HPLC analysis of the crudereaction mixture revealed 95-100% assay yield (1.52-1.60 kg anilineproduct). The reaction mixture was distilled under reduced pressure(typically 250-300 mbar) at a batch temperature of 50±5° C. until thetotal reaction volume was approximately 8.00 L (4.00 Vol). The batch wassubjected to a constant-volume distillation at 50±5° C., 250-300 mbar,by adding heptane to control the total batch volume. After approximately8.00 L (4.00 Vol) of heptane were added, GC analysis indicated that thesolvent composition was approximately 50% isopropyl acetate, 50%heptane. Vacuum was broken, and the internal batch temperature wasmaintained at 50±5° C. To the reaction mixture was added a slurry ofseed (20.0 grams of product methyl4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate, in a solvent mixtureof 80 mL heptane and 20 mL isopropyl acetate). The resulting slurry wasallowed to stir at 50±5° C. for 2±1 hours, then cooled to 20±5° C. over2.5±1.0 h. Additional heptane (24.0 L, 12.0 Vol) was added dropwise over2 hours, and the batch was allowed to stir at 20±5° C. for 1 hours(typically overnight). Quantitative HPLC analysis of this filteredsupernatant revealed <5 mg/mL product in solution, and the productcrystals were 50-400 μm birefringent rods. The reaction slurry wasfiltered at 20° C. onto a filter cloth, and the cake wasdisplacement-washed with heptane (6.00 L, 2.00 Vol). The cake was driedon the filter under nitrogen sweep at ambient temperature for >4 hours,until sample dryness was confirmed by LOD analysis (indicated <1.0 wt %loss). The product methyl4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (1.56 kg) wasisolated as a pale-yellow powder in 86% yield at 99.8 wt % by HPLC with100.0 LCAP₂₁₀. [Analysis of the combined filtrates and washes revealed108 grams (7.0%) of product lost to the mother liquors. The remainingmass balance is comprised of product hold-up in the reactor (fouling).]¹H NMR (DMSO-d₆, 400 MHz) δ: 6.81 (dd, J=7.53, 7.82 Hz, 1H), 6.67 (m,1H), 6.49 (m, 1H), 5.04 (s, 2H), 3.58 (s, 3H), 3.45 (m, 2H), 3.34 (m,4H), 2.33 (m, 4H). ¹⁹F NMR (d₆-DMSO, 376 MHz) δ: −140.2. ¹³C NMR(d₆-DMSO, 125 MHz) δ: 155.0, 150.5, 148.2, 136.2 (m), 123.7 (m), 117.6,115.1, 73.7, 54.9 (m), 52.1 (m), 43.4. mp=89.2° C.

Omecamtiv Mecarbil Dihydrochloride Hydrate Procedure

To a 15 L glass lined reactor were charged methyl4-(3-amino-2-fluoro-benzyl)piperazine-1-carboxylate (1,202 g, 4.50 mol),phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (1,444 g, 5.40mol), and tetrahydrofuran (4.81 L). The resulting slurry was agitatedunder a nitrogen sweep and N,N-diisopropylethylamine (1,019 L, 5.85 mol)was then charged to the slurry which resulted in a brown solution. Thetemperature of the solution was increased to 65° C. and agitated for 22h, until <1% AUC piperazine aniline remained by HPLC analysis.

The batch was cooled to 50° C. and distilled under reduced pressurewhile maintaining the internal temperature of the vessel below 50° C. byadjusting vacuum pressure. 2-Propanol was added with residual vacuum ata rate to maintain a constant volume in the 15 L reactor. A total of10.5 kg of 2-propanol was required to achieve <5% THF by GC. Water (2.77kg) was then charged to the reactor followed by the addition of 6N HCl(1.98 kg) at a rate to maintain the internal temperature below 60° C.The reactor was brought to ambient pressure under a nitrogen sweep. Thesolution was then heated to 60° C., and transferred to a 60 L glasslined reactor through an inline filter. The 15 L reactor was then rinsedwith 1:1 water/2-propanol (1.2 L) which was sent through the inlinefilter to the 60 L reactor.

The 60 L reactor was adjusted to 45° C. and a slurry of seed (114 g,0.23 mol) in 2-propanol (0.35 L) was added to the reactor resulting in aslurry. The batch was aged at 45° C. for 1 h, followed by the additionof 2-propanol (3.97 kg) through an inline filter over 2 h. The batch washeated to 55° C. over 1 h and held for 0.25 h, then cooled back to 45°C. over 1 h and held overnight at 45° C. 2-propanol (11.71 kg) was thenadded through an inline filter to the batch over 3 h. The batch was agedfor 1 h and then cooled to 20° C. over 2 h and held at 20° C. for 0.5 h.The batch was then recirculated though a wet mill affixed with 1-mediumand 2-fine rotor-stators operating at 56 Hz for 2.15 h, until no furtherparticle size reduction was observed by microscopy.

The batch was then filtered through a 20″ Hastelloy® filter fitted witha 12 um filter cloth under 500 torr vacuum. A wash solution of 95:52-propanol:water (1.82 L) was charged through an inline filter to the 60L reactor, then onto the filter. A second wash of 2-propanol (2.85 L)was charged through an inline filter to the 60 L reactor, then onto thefilter. The batch was then dried under 5 psi humidified nitrogenpressure until <5,000 ppm 2-propanol, and 2.5-5% water remained. Thefinal solid was discharged from the filter to afford 2.09 kg of methyl4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylateas an off-white crystalline solid in 89% yield at 99.88 wt % by HPLC,100.0% AUC. Total losses to liquors was 0.10 kg (4.7%).

DSC: T_(onset)=61.7° C., T_(max)=95.0° C.; TGA=2.2%, degradationonset=222° C.; ¹H HMR (D₂O, 500 MHz) δ 8.87 (s, 1H), 8.18 (d, J=8.9 Hz,1H), 7.83 (t, J=7.5 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 2H),4.48 (s, 2H), 4.24 (br s, 2H), 3.73 (s, 3H), 3.31 (br s, 6H), 2.68 (s,3H); ¹³C HMR (D₂O, 150 MHz) δ 156.8, 154.2, 153.9 (J=249 Hz), 147.8,136.3, 136.1, 130.1, 129.4, 128.0, 127.2, 125.5 (J=11.8 Hz), 125.1(J=4.2 Hz), 116.1 (J=13.5 Hz), 53.54, 53.52, 53.49, 50.9, 40.5, 18.2.

Comparative Example 1: Immediate Release Formulation

TABLE 1 Theo, Theo, Material w/w % mg/unit Intra-granulation omecamtivmecarbil di hydrochloride hydrate 12.28 30.70 Fumaric acid 12.28 30.70Microcrystalline cellulose, Avicel ® PH 101 38.00 95.00 Lactosemonohydrate, Impalpable 313 29.94 74.85 Hydroxypropyl cellulose, KlucelEXF 2.00 5.00 Croscarmellose sodium, Ac-Di-Sol 2.50 6.25Extra-granulation Croscarmellose sodium, Ac-Di-Sol 2.50 6.25 Magnesiumstearate 0.50 1.25 Total 100.00% 250.00

Immediate release formulation comprising the above components wereprepared according to the process outlined in FIG. 1.

Example 1: Prototype Modified Release Formulation

Omecamtiv mecarbil prototype modified release (“MR”) matrix tabletformulation consists of omecamtiv mecarbil anhydrate free base (active),Methocel™ K100 M CR (control release agent), citric acid monohydrate (pHmodulation agent), microcrystalline cellulose and lactose monohydrate(filler), Methocel™ E5 LV (binder), and magnesium stearate (lubricant).Table 1 shows the prototype formulation compositions. The prototype MRmatrix tablets are manufactured via a conventional high shear wetgranulation process. This includes screening omecamtiv mecarbilanhydrate, lactose monohydrate FFL 316, microcrystalline cellulose,Avicel® PH 101, Methocel™ K100 M CR, and citric acid monohydrate througha #20 mesh US standard screen followed by charging the screenedmaterials into an appropriate size of high shear granulator, where thematerials are dry mixed for a specific time at the pre-determinedimpeller and chopper speeds (granulator size, dry mixing time, impellerand chopper speeds are scale-dependent parameters). The wet granulationprocess starts with the addition of pre-prepared 3% w/w Methocel™ E5solution using a pre-selected spray nozzle at a pre-determined spraypressure and spray rate. The pre-determined impeller and chopper speedsare used during the wet granulation process (the nozzle size, sprayrate, spray pressure, impeller, and chopper speeds are scale-dependentparameters). After wet granulation, the wet mass is dried using a fluidbed drying process with a target of LOD (loss on drying) of <2.4% (fluidbed granulator is scale-dependent The dried granulation is then milledusing a Fitzmill® using a pre-determined speed and screen size(Fitzmill® model, speed and screen size are scale-dependent parameters).After milling, the milled dry granulation is lubricated using thepre-screened (#30 mesh) magnesium stearate in a tumble blender at apre-determined speed, time, and fill-volume (tumble blender model,blending speed, time, and fill-volume are scale-dependent parameters).After the lubrication, the final blend is compressed into MR matrixtablets using a rotary tablet press at a target tablet hardness of 10-14kp.

The following case study exemplifies an embodiment of a manufacturingprocess of omecamtiv mecarbil anhydrate 25 mg prototype MR matrixtablets. The target batch size is 60 kg. the raw materials billed forthe batch is 4.30 kg of omecamtiv mecarbil anhydrate (approximately14.7% excess to compensate the de-lumping loss), 10.1 kg ofmicrocrystalline cellulose, Avicel® PH101, 8.12 kg of lactosemonohydrate FFL316, 7.50 kg of citric acid monohydrate, 30.0 kg ofMethocel™ K100 M CR, 0.6 kg Methocel™ E5 LV (excess binder solutionprepared, but the exact amount is added during wet granulation process.The residual binder solution is discarded as the waste), 19.4 kg ofpurified water, and 0.30 kg of magnesium stearate.

Binder solution preparation: Filling 19.4 kg of purified water into a19-gallon portable mixing kettle and then adding 0.6 kg of Methocel™ E5LV slowly and steadily.

Loading the raw materials into the Diosna P-300 high shear granulator:Manually loading the majority of screened lactose monohydrate andmicrocrystalline cellulose into granulator bowl. Manually loading citricacid monohydrate into the bowl. Manually loading milled omecamtivmecarbil anhydrate into the bowl. Manually loading screened Methocel™K100 M CR into the bowl.

Transferring the binder solution: Transferring the binder solution intothe solution tank.

Wet granulation: Transferring 6.60 kg of binder solution into granulatorbowl.

Fluid bed drying: Dry the granulation.

Dry milling: Manually charging the dried granulation and beginning tomill.

Lubrication: Loading approximately half of the milled granulation into aV-blender and then adding the magnesium stearate in, adding theremaining half of milled granulation in.

Compression: The final blend is manually charged into the hopper ofrotary tablet press equipped with 7/16″ round, standard cup, concave,plain tooling. The target tablet weight is 400 mg with a range of370-430 mg. the target hardness is 12 kp with a range of 10-14 kp.

Prototype MR Matrix Tablet Formulation Composition

12.5 mg 25.0 mg Component % w/w % w/w omecamtiv mecarbil anhydrate 3.1256.25 MCC, Avicel ® PH101 16.88 16.88 Lactose monohydrate FFL 316 18.2513.55 Citric acid Monohydrate 6.25 12.50 Methocel ™ K100 M CR 50.0050.00 Methocel ™ E5 LV 5.00 0.33 Magnesium stearate 0.50 0.50

Matrix Modified Release Tablet: General Method

A process for modified release (“MR”) matrix tablet manufacturing via adry granulation process is described herein. Omecamtiv mecarbildihydrochloride hydrate, microcrystalline cellulose, lactosemonohydrate, Methocel™ K100 M CR/Methocel™ K100 LV CR, and fumaric acidare screened and then charged into a tumble blender and blended therefor a specific time at a pre-determined speed (blender size, blendingspeed, and blending time are scale-dependent parameters). The blendedmaterials are lubricated in the same blender using the pre-screenedmagnesium stearate. The lubricated blend is then roller compacted andmilled. The resultant granulation is lubricated in a tumble blenderusing the pre-screened magnesium stearate. The lubricated granulation iscompressed into modified release matrix tablets using a rotary tabletpress with a target tablet hardness of 10 kp.

Example 2: Omecamtiv Mecarbil dihydrochloride hydrate 25 MCI SlowRelease MR Matrix Tablets (MTX-F1)

The target batch size is 5 kg the raw materials billed for the batch is306.50 g of omecamtiv mecarbil dihydrochloride hydrate, 1840.50 g ofmicrocrystalline cellulose, Avicel® PH102, 920.0 g of lactosemonohydrate, FFL316, 383.0 g of fumaric acid, 1500.0 g of Methocel™ K100M CR, 35 g of intra-granular magnesium stearate (10 g excess fromtheoretical batch size to accommodate the screening process loss), and35 g of extra-granular magnesium stearate (10 g excess from theoreticalbatch size to accommodate the screening process loss).

Powder Screening: Step 1. Screening 1840.5 g of microcrystallinecellulose, Avicel® PH102, 306.50 g of omecamtiv mecarbil dihydrochloridehydrate, 383.11 g of fumaric acid, 920.0 g of lactose monohydrate,FFL316, and 1500.0 g of Methocel™ K100 M CR through a 20 mesh USstandard sieve into a double PE bag.

Powder Blending: Step 2. Charging the screened blend from Step 1 into a20 L Bohle blender and blending for 30 minutes at a speed of 20 rpm.

Powder Lubrication: Step 3. Screening the entire amount ofintra-granular magnesium stearate through a 60 mesh US standard sieveand weighing out the required amount of sieved magnesium stearate, 25.0g, into a an appropriate container. Step 4. Manually pre-mixing therequired amount of sieved magnesium stearate with approximately 1× to 3×of powder blend from Step 2 in the same container for approximately 60seconds. Step 5. Charging the pre-mix blend from Step 4 back into thepowder blend in Step 2. Step 6. Blending the powder blend from Step 2for 4 minutes at a blending speed of 20 rpm. Step 7. Discharging thelubricated powder blend into an appropriate container.

Dry granulation: Step 8. Charging the lubricated powder blend from Step7 into Gerteis roller compactor hopper and start dry granulationmanufacturing using the following process parameters. Roll Surface:Knurl; Agitator speed: 15 rpm; Roll force: 7.0 kn/cm; Roll speed: 2 rpm;Roll gap: 2.5 mm; Gap control: ON; Screen size: 1 mm; Clearance betweengranulator and screen: 2.0 mm; Granulator speed: 80 rpm; and Granulatorrotation angle: 200/230 degree. Step 9. Discharging the granulation intoan appropriate container and weigh the net weight, which is 4844 g.

Granulation lubrication: Step 10. Calculating the required amount ofmagnesium stearate needed for the granulation blend, which is 24.34 g.Step 11. Screening the entire amount of extra-granular magnesiumstearate through a 60 mesh US standard sieve and weighing out therequired amount of screened magnesium stearate in Step 10. Step 12.Charging the granulation from Step 9 into a 20 liter Bohle blender. Step13. Manually pre-mixing the screened extra-granular magnesium stearatefrom Step 11 with 1× to 3× of granulation from Step 12 in an appropriatecontainer for about 60 seconds. Step 14. Charging the pre-mixed blendfrom Step 13 back to the blender in Step 12. Step 15. Blending thegranulation blend from Step 12 for 5 minutes at a blending speed of 20rpm. Step 16. Discharging the granulation blend from Step 15 into anappropriate container.

Tablet compression: Step 17. The final granulation blend from Step 16 ismanually charged into the hopper of rotary tablet press Korsch XL100equipped with 7/16″ round, standard cup, concave, plain tooling. Step18. The compression starts at a speed of 25 rpm to dial in the targettablet weight and hardness. The target tablet weight is 500 mg with arange of 475-525 mg. the target hardness is 10 kp with a range of 6-14kp. The total number of tablet manufactured is 9,115.

TABLE 2 Composition of omecamtiv mecarbil dihydrochloride hydrate 25 mgslow release MR matrix tablets MTX-F1 in accordance with the disclosure25 mg Slow release Theo. Theo. Material w/w (%) mg/unit Intra-granularomecamtiv mecarbil Di-HCl hydrate 6.13 30.65 Methocel ™ K100 M Prem CR30.00 150.00 Microcrystalline cellulose, PH 102 36.81 184.05 Lactosemonohydrate, FF 316 18.40 92.00 Fumaric acid 7.66 38.30 Magnesiumstearate 0.50 2.50 Sub Total 99.50 497.50 Extra-granular Magnesiumstearate 0.50 2.50 Total/batch weight 100.00 500.00

Matrix modified release tablets comprising the above components wereprepared according to the process outlined in FIG. 2. Note: In someembodiments, the concentration range is 15%-80% for Methocel™ K100 M CR,0%-70% for microcrystalline cellulose, Avicel® PH102, 0%-70% for lactosemonohydrate, FFL316, 3.83%-50% for fumaric acid, 0%-2% forintra-granular magnesium stearate, and 0%-2% for extra-granularmagnesium stearate.

Example 3

TABLE 3 Composition of omecamtiv mecarbil dihydrochloride hydrate 25 mgfast release MR matrix tablets MTX-F2 in accordance with the disclosure25 mg Fast release Theo. Theo. Material w/w (%) mg/unit Intra-granularomecamtiv mecarbil Di-HCl hydrate 6.13 30.65 Methocel ™ K100 M Prem CR5.00 25.00 Methocel ™ K100 LV Prem CR 20.00 100.00 Microcrystallinecellulose, PH 102 40.14 200.70 Lactose monohydrate, FF 316 20.07 100.35Fumaric acid 7.66 38.30 Magnesium stearate 0.50 2.50 Sub Total 99.50497.50 Extra-granular Magnesium stearate 0.50 2.50 Total/batch weight100.00 500.00

Matrix modified release tablets comprising the above components wereprepared according to the process outlined in FIG. 3. Note: In someembodiments, the concentration range is 0%-15% for Methocel™ K100 M CR,15%-50% for Methocel™ K100 LV, 0%-75% for microcrystalline cellulose,Avicel® PH102, 0%-75% for lactose monohydrate, FFL316, 3.83%-50% forfumaric acid, 0%-2% for intra-granular magnesium stearate, and 0%-2% forextra-granular magnesium stearate.

Example 4

TABLE 4 Composition of omecamtiv mecarbil dihydrochloride hydrate 75 mgslow release MR matrix tablets MTX-F3 in accordance with the disclosure75 mg Theo. Theo. Material w/w (%) mg/unit Intra-granular omecamtivmecarbil Di-HCl hydrate 18.37 91.85 Methocel ™ K100 M Prem CR 30.00150.00 Microcrystalline cellulose, PH 102 24.20 121.00 Lactosemonohydrate, FF 316 8.07 40.35 Fumaric acid 18.37 91.85 Magnesiumstearate 0.50 2.50 Sub Total 99.50 497.50 Extra-granular Magnesiumstearate 0.50 2.50 Total/batch weight 100.00 500.00

Matrix modified release tablets comprising the above components wereprepared according to the process outlined in FIG. 3. Note: In someembodiments, the concentration range is 15%-80% for Methocel™ K100 M CR,0%-65% for microcrystalline cellulose, Avicel® PH102, 0%-65% for lactosemonohydrate, FFL316, 3.83%-50% for fumaric acid, 0%-2% forintra-granular magnesium stearate, and 0%-2% for extra-granularmagnesium stearate.

Example 5

TABLE 5 Composition of omecamtiv mecarbil dihydrochloride hydrate 75 mgfast release MR matrix tablets MTX-F4 in accordance with the disclosure75 mg Fast release Theo. Theo. Material w/w (%) mg/unit Intra-granularomecamtiv mecarbil Di-HCl hydrate 18.37 91.85 Methocel ™ K100 M Prem CR5.00 25.00 Methocel ™ K100 LV Prem CR 20.00 100.00 Microcrystallinecellulose, PH 102 27.95 200.70 Lactose monohydrate, FF 316 9.31 100.35Fumaric acid 18.37 91.85 Magnesium stearate 0.50 2.50 Sub Total 99.50497.50 Extra-granular Magnesium stearate 0.50 2.50 Total/batch weight100.00 500.00

Matrix modified release tablets comprising the above components wereprepared according to the process outlined in FIG. 3. Note: In someembodiments, the concentration range is 0%-15% for Methocel™ K100 M CR,15%-50% for Methocel™ K100 LV, 0%-65% for microcrystalline cellulose,Avicel® PH102, 0%-65% for lactose monohydrate, FFL316, 3.83%-50% forfumaric acid, 0%-2% for intra-granular magnesium stearate, and 0%-2% forextra-granular magnesium stearate.

pH Dependent Release Profiles

A formulation of omecamtiv mecarbil hemihydrate (free base) anddihydrochloride hydrate (Form A) were prepared having the followingcomponents, all components reported as a w/w %:

Free Base (75 mg matrix tablet) Active granulation: 15.37% free base;30% hypromellose, HPMC K100 MPrem CR; 10% citric acid monohydrate;11.88% microcrystalline cellulose, Avicel PH 101; 6.75% lactosemonohydrate, FastFlo 316; 12.5% purified water; and Citric Acidgranulation: 20% citric acid monohydrate; 5% microcrystalline cellulose,Avicel PH 101; and 1% magnesium stearate, non-bovine.Form A (75 mg matrix tablet) Intra-granulation: 18.37% Form A; 30%hypromellose, HPMC K100 MPrem CR; 0.50% magnesium stearate; andExtra-granulation: 16.88% microcrystalline cellulose, Avicel PH 101;18.37% citric acid anhydrous; and 0.5% magnesium stearate, non-bovine.

The formulations were tested at pH 2 and pH 6.8 and the amount of drugreleased over time was measured. The results of this drug releaseprofile are shown in FIG. 6.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed:
 1. A pharmaceutical formulation comprising: omecamtivmecarbil, or a pharmaceutically acceptable salt, a pharmaceuticallyacceptable hydrate, or a pharmaceutically acceptable hydrate of apharmaceutically acceptable salt thereof; a control release agent; a pHmodifying agent; a filler; and a lubricant.
 2. The pharmaceuticalformulation of claim 1, wherein the omecamtiv mecarbil is present asomecamtiv mecarbil dihydrochloride hydrate.
 3. A pharmaceuticalformulation according to claim 1 or 2, wherein the pH modifying agent isselected from maleic acid, citric acid, tartaric acid, pamoic acid,fumaric acid, salicylic acid, 2,6-diaminohexanoic acid, camphorsulfonicacid, glycerophosphoric acid, 2-hydroxyethanesulfonic acid, isethionicacid, succinic acid, carbonic acid, p-toluenesulfonic acid, asparticacid, 8-chlorotheophylline, benezenesulfonic acid, malic acid, oroticacid, oxalic acid, benzoic acid, 2-naphthalenesulfonic acid, stearicacid, adipic acid, p-amino-salicylic acid, 5-aminoslicylic acid,ascorbic acid, sulfuric acid, cyclamic acid, sodium lauryl sulfate,glucoheptonic acid, glucuronic acid, glycine, sulfuric acid, mandelicacid, 1,5-naphthalenedisulfonic acid, nicotinic acid, oleic acid,2-oxoglutaric acid, pyridoxal 5-phosphate, undecanoic acid,p-acetamidobenzoic acid, o-acetamidobenzoic acid, m-acetamidobenzoicacid, N-acetyl-L-aspartic acid, camphoric acid, dehydrocholic acid,malonic acid, edetic acid, ethylenediainetetraacetic acid, ethylsulfuricacid, hydroxyphenylbenzoylbenzoic acid, glutamic acid, glycyrrhizicacid, 4-hexylresorcinol, hippuric acid, p-phenolsulfonic acid,4-hydroxybenzoic acid, 3-hydroxybenzoic acid, 3-hydroxy-2-naphthoicacid, 1-hydroxy-2naphthoic acid, lactobionic acid, 3′-adenylic acid,5′-adenylic acid, mucic acid, galactaric acid, pantothenic acid, pecticacid, polygalacturonic acid, 5-sulfosalicylic acid,1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurine-7-propanesulfonic acid,terephthalic acid, 1-hydroxy-2-naphthoic acid, and any combinationthereof.
 4. A pharmaceutical formulation according to claim 3, whereinthe pH modifying agent is selected from maleic acid, citric acid, malicacid, fumaric acid, sulfuric acid, tartaric acid, lactoic acid,salicylic acid, aspartic acid, aminosalicylic acid, malonic acid,glutamic acid, and any combination thereof.
 5. A pharmaceuticalformulation according to claim 4, wherein the pH modifying agent isfumaric acid.
 6. A pharmaceutical formulation according to any one ofclaims 1-5, wherein the filler is selected from starches, lactose,mannitol, cellulose derivatives, calcium phosphate, a sugar, and anycombination thereof.
 7. A pharmaceutical formulation according to anyone of claims 1-6, wherein the control release agent is Methocel™ K100 MPrem CR.
 8. A pharmaceutical formulation according to any one of claims1-6, wherein the control release agent is Methocel™ K100 LV Prem CR. 9.A pharmaceutical formulation according to any one of claims 1-6, whereinthe control release agent is a mixture of Methocel™ K100 M Prem CR andMethocel™ K100 LV Prem CR.
 10. A pharmaceutical formulation according toany one of claims 1-9, wherein the filler is a combination ofmicrocrystalline cellulose and lactose monohydrate.
 11. A pharmaceuticalformulation according to any one of claims 1-10, wherein the lubricantis magnesium stearate.
 12. A pharmaceutical formulation according to anyone of claims 1-11, wherein the formulation is in the form of a tablet.13. The pharmaceutical formulation according to any one of claims 1-12comprising: 3-30% w/w of omecamtiv mecarbil, or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable hydrate, or apharmaceutically acceptable hydrate of a pharmaceutically acceptablesalt thereof; 15-35% w/w control release agent; 20-45% w/w pH modifyingagent; 25-65% w/w filler; and 0.1-1.0% w/w lubricant.
 14. A process formaking a pharmaceutical formulation according to claim 1, comprising:blending a mixture comprising omecamtiv mecarbil, or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable hydrate, or apharmaceutically acceptable hydrate of a pharmaceutically acceptablesalt thereof, a control release agent, a pH modifying agent, and afiller; lubricating the blended mixture using a lubricant; granulatingthe lubricated blend; lubricating the resultant granulation using thelubricant; and compressing the lubricated granulation into desired form.15. The process of claim 14, wherein the omecamtiv mecarbil is presentas omecamtiv mecarbil dihydrochloride hydrate.
 16. A pharmaceuticalformulation prepared by the process of claim 14 or
 15. 17. A method oftreating a disease selected from acute heart failure and chronic heartfailure, comprising administering a pharmaceutical formulation accordingto any one of claim 1-13 or 16 to a patient in need thereof.
 18. Apharmaceutical formulation according to any one of claims 1-13, whereinthe exposure of omecamtiv mecarbil from two to twelve hours after dosingin humans remains between 40 and 70 ng/ml.
 19. The pharmaceuticalcomposition according to claim 18, wherein the exposure of omecamtivmecarbil from two to twelve hours after dosing in humans remains between40 and 55 ng/ml.
 20. A pharmaceutical composition according to any oneof claims 1-13, wherein the omecamtiv mecarbil is released in thefollowing intervals: ≤30% dose dissolved at 1 hour; 30-75% dosedissolved at 3 hours; and ≥80% dose dissolved at 12 hours.
 21. Apharmaceutical composition according to any one of claims 1-13, whereinthe omecamtiv mecarbil is released in the following intervals: ≤30% dosedissolved at 2 hours; 30-75% dose dissolved at 6 hours; and ≥80% dosedissolved at 16 hours.